Numerous investigators have shown that declining immunologic vigor is a regular concomitant of aging. We discovered that this aspect of aging is more prominent in certain strains of mice than others and that it is accompanied by increasing autoimmunity. These changes are accelerated by thymectomy. In mice where immunologic deficiency and autoimmunity are observed during aging, preliminary evidence indicates associated thymic involution, loss of thymic dependent cells and decreased cellular mediated immune functions. The objectives of our investigations are: 1) to further define the age-related changes in the function of lymphocytes subpopulations and 2) to test the relative capacities of thymus stroma or thymus in millipore chambers, stem cells and immunocompetent cells of young and aging autoimmune susceptible and resistant strains to restore immune functions and prolong life in neonatally thymectomized and aging mice. Thus the meaning of involution of the thymus and its system with respect to development of immune deficiency, autoimmunity, and malignancy with aging can be effectively assessed at the cellular level and, 3) to analyze the relationship between histocompatibility genes, longevity and tumor-susceptibility. Genetic experiments will be performed to extend the observations of the advantage of heterozygosis at H-2 loci in survival. F1 and F2 hybrids and backcrosses using long-and short-lived mice will be useful for analysis of cellular deficits, autoantibodies, tumor development, survival and H-2 genotypes. These experiments will attempt to show that thymic involution may influence pathogenesis of diseases of aging whereas etiology requires a genetically programmed system involving genes linked to the major transplantation loci. Understanding of these relationships should ultimately help prolong useful life in man.